Ask the CLL Expert

Ask the CLL Expert – Dr. Sharman

Transcript:

Recorded on: September 27, 2018

Andrew Schorr:
Greetings to this live Ask the Expert program for those of us dealing with CLL. I’m Andrew Schorr from Patient Power. Welcome to this Patient Empowerment Network program with financial support from AbbVie and Pharmacyclics. Thank you so much for being with us.

We have a wonderful expert with us today who is so knowledgeable about this, and that is Dr. Jeff Sharman. Dr. Sharman is the medical oncologist, of course, one of them at the Willamette Valley Cancer Institute and Research Center in Oregon. He’s also the medical director for hematology research at the US Oncology Network with oncologists all across the country. Jeff, welcome back to our program.

Dr. Sharman:
Thank you so much. It’s nice to be here today.

Andrew Schorr:
Okay. Let’s get started. We have a lot of questions coming in, and if you, our viewer, have an additional question send it to cll@patientpower.info and we’ll cover as much as we can in the next half hour.

Here’s a question that came in based on news events that people follow related to CLL, and this is from William. He says, I heard there’s a new drug approved for CLL, duvelisib. Can you tell more about this? Where does it fit in in the CLL landscape?

Dr. Sharman:
Absolutely. Duvelisib is another PI3 inhibitor. It has considerable molecular similarity to idelalisib, which was the first in class medication approved amongst the PI3 inhibitors a few years ago. This molecule has considerable both biochemical similarity, structural similarity but also quite a bit of clinical similarity. So when you look at the patient population in which it’s approved, similar clinical trial designs led to approval, and so as a result it’s sort of in the third‑line setting that you could use it.

It is a‑‑the drug class is a sort of the whole PI3 family of which there’s a growing number. There’s idelalisib, umbralisib is in late‑stage clinical trials. Copanlisib is approved in follicular lymphoma but not CLL. And as a family they tend to be utilized less frequently than the BTK inhibitors such as ibrutinib and to some degree less frequently than venetoclax, as well, the Bcl‑2 family, and that has to do with some of the side effects, that there is, a frequency of diarrhea, LFT abnormalities and so forth. So it follows on the heels of idelalisib, and I would say has more similarities than differences.

Andrew Schorr:
Okay. Let’s go on. You mention about side effects. People ask about that all the time, so here’s a question from Judy. She says, I’m not able to get an answer from my husband’s oncologist regarding ibrutinib and severe body cramping. Have there been any reports showing this is a possible side effect from ibrutinib?

Dr. Sharman:
Absolutely, it is. It is‑‑well, absolutely possible, let’s say that. It actually is what I would say one of the most common side effects that I encounter as a limitation for ibrutinib. The medical term for it is arthralgias, which is sort of translates into joint pains. Sometimes you’ll also see actual cramps or spasms. I’ve had patients’ hands lock up when they’re driving sometimes, which can be a little bit concerning.

There is I think considerable question in the field. There are differences amongst thought leaders on this as to whether‑‑how to best manage it.

There’s some studies that suggest that lower dosages may‑‑after a patient has been on ibrutinib for a length of time you may be able to get away with lower dosages. Those pieces of clinical trial data are not as large and not as well validated, so I think it’s still in the hypothesis‑generating mode, but there’s some data that suggest you could do it. And if the choice was lower dose of ibrutinib or no dose of ibrutinib, I would probably go with a lower dose.

The other potential solution now is acalabrutinib, which is a second BTK inhibitor approved. It is approved by the FDA for mantle cell lymphoma. However, a lot of the clinical trials are in chronic lymphocytic leukemia, and there have been studies that looked at patients who have limited tolerance of ibrutinib, and in many cases they were able to go on acalabrutinib without a recurrence of the same side effects.

So that’s another possibility. It is in the NCCN guidelines that for those patients who have intolerance of ibrutinib consider acalabrutinib. So whether it’s dose reduction or drug substitution, those are sometimes two ways that I use to get around that scenario.

Andrew Schorr:
Okay. Now, we should be clear that acalabrutinib is not yet approved for CLL. Does it seem like that’s forthcoming? I mean, nobody can guess the FDA, but.

Dr. Sharman:
Yeah. So the clinical trial that will lead to approval, presumptive approval, was a head‑to‑head comparison against investigators’ choice of bendamustine rituximab or idelalisib rituximab, and that study is fully accrued and waiting for end points.

And I think that the feeling would be that should be a positive test and that it would eventually get CLL approval. Most of the studies have been done in CLL. It’s just the mantle cell indication came along more quickly.

Andrew Schorr:
Okay. All right. A lot of people worry about other side effects like fatigue, of course, in CLL. So here’s a question from Patty. She says, I’ve been taking 60 milligrams of Vyvanse, which is often used for ADHD, for extreme fatigue that she struggles with. And she says her blood pressure is elevated, and she’s read that that can be a side effect of Vyvanse. Are there any new or additional medications that can be used to treat fatigue without the worry of high blood pressure?

Dr. Sharman:
The way I would approach that situation, fatigue‑‑what I don’t know about this particular patient, is this fatigue that is attributable to the CLL or fatigue that’s attributable to medications?

CLL fatigue is probably one of the most bothersome sort of clinical realities, and for some patients even though they may not meet other treatment criteria such as rapid rise in white blood cell counts, systematic (?) inaudible adenopathy, marrow dysfunction. Sometimes fatigue is so debilitating that you need to do treatment for it. In the 2008 guidelines, fatigue was one of the‑‑it was like the sixth indication for when you treat CLL.

And I’ve seen some patients, you know, one immediately jumps to my mind. He’s clinician himself, very busy individual, likes to surf and so on and so forth, but his CLL left him so fatigued that he had to cut back on clinical work and so forth. And getting his CLL under control really made a huge difference for him. So in the setting of CLL I think that you may wish to consider talking to your doctor about going ahead and treating.

I find those are difficult, difficult discussions because if you don’t have the more classic indications for therapy it’s hard to know. Because fatigue can be a number of things. It can be thyroid dysfunction. It can be hormone imbalance with other hormones. It can be nutrient deficiencies and so forth.

Andrew Schorr:
It could be having three kids.

Dr. Sharman:
Absolutely.

Andrew Schorr:
Yeah, I know. Lots of things.

Here’s another question from Bob. Bob wants to know, will approaches likely change for first‑line treatment, for instance venetoclax, or Venclexta, within the next two years? You have ibrutinib first line.

Dr. Sharman:
Yeah.

Andrew Schorr:
You have FCR that’s been around. You have idelalisib I think could be used first line.

Dr. Sharman:
Actually, idelalisib is specifically contraindicated for first‑line therapy because of side effects.

Andrew Schorr:
Okay. So what about first‑line therapies, Jeff? Where are we there and what’s coming?

Dr. Sharman:
Yeah, so you’re kind of in this bind currently where your choices are chemoimmunotherapy or targeted therapy, and both of them have strengths and weaknesses. The strength of chemoimmun0therapy is that you give treatment for a fixed duration of time, and then you get treatment‑free interval that in properly selected patients should be measured in multiple years.

Andrew Schorr:
I went 17 years.

Dr. Sharman:
Yeah, absolutely. So effective therapy in appropriately selected patients. Now, when I say appropriately selected patients, that does get into some of the nuance about FISH changes and IGHV mutation, and I will tell you even amongst thought leaders in the field there’s some debate as to where you draw the line. Some patients are more suitable for ibrutinib either because of co‑morbidities or wish to avoid chemotherapy, but at least as of today ibrutinib is something you start and then stay on indefinitely.

And per the prior question, some patients have difficulties with that, whether it’s arthralgias or bruising bleeding and so forth. The medication you made mention of I think is the frontline therapy that may have the most profound impact on treatment selection in the next two years.

Andrew Schorr:
Venetoclax.

Dr. Sharman:
So the German Research Group, which is really just absolutely one of the best out there, have fully enrolled a clinical trial of obinutuzumab venetoclax versus chlorambucil and obinutuzumab, and I have to believe that that is going to result in a superior outcome for the venetoclax arm and that we will have the combination of obinutuzumab venetoclax for front‑line setting.

And what’s really appealing about that is that is one year of treatment and then treatment is suspended and stopped. And though we haven’t compared that to more traditional BR or FCR, I think it would be a highly effective regimen. We are currently conducting a study in the United States in our research network looking at the combination of obinutuzumab and venetoclax, and what I like about our study is we give‑‑for the listeners who might not be familiar with venetoclax, starting venetoclax is a little bit clunky because it works so quickly we have to be careful about a condition called tumor lysis syndrome, which is if you kill too much cancer cells too quickly that can cause some dangerous conditions, and venetoclax does do that.

And so what we’re doing is we’re giving two months of obinutuzumab and sort of getting rid of the bulk of the CLL and then starting the venetoclax hopefully under much safer conditions because, you know, in the Pacific Northwest we would say you can’t have forest fires if you don’t have any trees. So if we get rid of all the CLL or a substantial fraction of it somebody is less likely to have tumor lysis. So I think that’s the approach that is probably the next up in frontline.

The one other thing that could potentially change is acalabrutinib has conducted a three‑arm study‑‑excuse me, Acerta with acalabrutinib, where they give‑‑it’s a three‑arm study with either chlorambucil Gazyva, acalabrutinib or acalabrutinib with Gazyva. And so does the addition of a C‑20 antibody make BTK work better, remains the question outstanding.

Andrew Schorr:
All right. Let me just explain things to people. I’ve been around this for a long time and Jeff deals with these acronyms all the time. So, first of all, Gazyva is the same as obinutuzumab.

Dr. Sharman:
Thank you, yes.

Andrew Schorr:
It’s an infused CD20 that’s targeting the CD protein on the B‑cell, the bad guy, and it is sort of I don’t know if you’d describe it as a more powerful version but it followed from Rituxan or rituximab that many of us had. So the idea is you have an infused therapy for some length of time, and then you may have an acalabrutinib with it or you may have a venetoclax or Venclexta with it. Get I get it right, Jeff?

Dr. Sharman:
Yes. And if I just had one other comment. I think there are a lost questions and certainly some very compelling data about the combination of a BTK inhibitor such as ibrutinib with a Bcl‑2 inhibitor such as venetoclax.

The challenge with that approach is it’s not approved in that combination and probably not going to be approved in the next two years unless the FDA does something that maybe I’m not anticipating at this point. That clinical trial that compares that to an existing standard is really only just getting off the ground now.

Andrew Schorr:
Okay. All right. Let’s buzz through some others. So John writes in, please compare purpose and benefit differences for FISH testing versus next generation sequencing. So maybe you could explain them too.

Dr. Sharman:
Absolutely. Thank you for the question. It’s one that I think is often very difficult to comprehend.

So a little bit of history here is that we’ve known for a long time with that patients with chronic lymphocytic leukemia have a pattern of common chromosome gains or losses, and we generally pay attention mostly to five separate categories.

There are some others that people sometimes look at, but ranging from sort of worst to best, worst is having a loss of chromosome 17p and P stands for petite arm, so part of the short arm of chromosome 17 is lost. 11q, Q stands for the long arm of chromosome 11. And then you have normal chromosomes or the addition of an extra chromosome 12 or the loss of a portion of chromosome 13 that kind of goes from worst to best. And that is very different than actual mutations in genes. So these are wholesale losses of large clunks of chromosomes.

And if you look at 17p the reason that 17p is bad is because there’s a particular gene there that’s very important called TP53, and you can actually have a mutation in TP53 without the presence of a chromosome loss. And so next generation sequencing looks at a host of additional genes that really until the last three to four years we didn’t know have the significance that they have. So TP53 is probably the most important, but you’re also seeing things such as SF3B1, NOTCH1, FA1. There are a variety of them that are out there. Some are better understood than others, and I think to some degree we’re still as a field even trying to figure out how best to integrate these into our clinical practice.

Andrew Schorr:
Okay. So would you recommend for the typical CLL patient that they have FISH testing, which tells you about the chromosomes, right?

Dr. Sharman:
Yeah.

Andrew Schorr:
And when do we need to do genomic testing to see with whether if any of those genes you just rattled off?

Dr. Sharman:
Yeah. So I can tell you about my own personal practice on that. I do think that the field, as I indicated before, is still trying to digest this, and a number of those specific mutations there isn’t necessarily super robust consensus as to when is the best time to draw those. So I’ll explain how I’ve thought through it, and if that resonates with you.

So my question in the previously untreated patient is whether or not this patient is suitable for chemoimmunotherapy. Previously I said appropriately selected patients get very long duration responses. I don’t want to give chemoimmunotherapy to a patient who is not going to get a sustained benefit.

If I anticipate that I’m only going to get 18 months benefit or two years of benefit, it is not worthwhile in my mind going through the chemotherapy to get that. I would rather put those patients on a tyrosine kinase inhibitor.

So my first stratification is the IGHV mutation status, and I would say in general if somebody’s mutated, which is the more favorable form, I would tend to err more on the side of chemoimmunotherapy for those patients. For those who are unmutated, which is the bad one, I would tend more towards targeted therapy. These aren’t totally black and white.

But my next level of stratification is FISH. So if you’ve got a bad FISH finding even if you’re in that favorable category I strip you out from the chemotherapy group.

Andrew Schorr:
So like if you had a 17p deletion, those chromosome deletions?

Dr. Sharman:
Yes. So if you’re mutated, which you think is good, but you also have a 17p, then I wouldn’t give that individual chemoimmunotherapy.

So if you have good IGHV, good FISH, good functional status and I’m thinking about give you FCR, that’s my final check is let’s make sure there’s not something lingering underneath the surface here that I don’t know about. So that’s where I check it.

Now, in the relapsed/refractory setting it is more the norm that those patients are almost all going on novel agents where those mutations are sort of a little bit less salient, so I don’t necessarily check that. However, I do recheck FISH with successive lines of therapy because that certainly can evolve. And to make things even a little bit worse now for somebody who has been on BTK, we need to think about BTK mutations and whether or not that patient might be suitable for a second‑ or third‑generation BTK inhibitor that can get around that.

Andrew Schorr:
Okay. And the genomic testing, when do you do that?

Dr. Sharman:
Well, so genomic testing is looking for those smaller mutations that don’t show up on FISH.

Andrew Schorr:
Okay.

Dr. Sharman:
So that’s my final break point before I would give somebody chemoimmunotherapy. But I will tell you, there are opinion leaders out there who will argue that chemoimmunotherapy is dead and shouldn’t do it.

Andrew Schorr:
Right. There are.

Dr. Sharman:
I’m in the camp that thinks there’s still purpose and value in doing that in appropriately selected patients.

Andrew Schorr:
Okay. Let’s get to some others. So Grant said he was diagnosed with a double diagnosis of diabetes and then, as he had additional testing, voila, he also had CLL. So he’s currently able to control his diabetes, and he’s in watch and wait for CLL. Is there any advice for me going forward with these two conditions? Diabetes and CLL.

Dr. Sharman:
It‑‑so I guess my question in such a circumstance is how is that CLL behaving. If he has a molecularly favorable CLL and he’s on watch and wait and things are simmering along, it may very well be that his diabetes poses a greater threat to his overall health than the CLL.

In contrast, somebody with an unmutated 17p deleted CLL, it’s the CLL that’s going to be more dangerous. Fortunately, the treatment interactions don’t overlap all that much. Sometimes with chemoimmunotherapy we give steroids, and that can be problematic for patients with diabetes, but I would manage them by and large independently.

Andrew Schorr:
Okay. We’ve gotten several other questions. Sharon, we got yours and Jason. They were asking about first line with ibrutinib, and I think we spoke about that and other choices that may have a different side effect profile if ibrutinib has a problem. And also Sharon had written in about she’s in this watch and wait and she wonders about FCR, and I think we can hear from you that FCR and maybe BR in some cases, which is this chemoimmunotherapy approach, still has a place in your mind. So, Sharon, stay tuned.

Lucy wrote in. She says, given the 17 (?) (p53) deletion what role does that play in determining the beginning of treatment for the CLL naive patient, and you were just saying probably not FCR or BR.

Dr. Sharman:
Yeah. Boy if somebody had a 17p deletion I would strongly advise against traditional chemoimmunotherapy. I think it can actually be more harm than good in some cases.

There is a more subtle point though that I would jump onto, which is what factor does it play in first‑line therapy. It’s not so much the agent. Some people feel like because they’ve got a 17p they need to jump into treatment sooner rather than later.

I will tell you I have several patients with 17p deleted CLL that I’ve been able to watch for years and years and years without treatment. The indications for starting therapy really remain the same. If I see somebody clearly heading towards treatment with a 17p I may start them a little bit earlier, but again some of these folks can be watched and wait quite well.

Andrew Schorr:
Okay. You’re a director of research, and we’re starting to hear about CRISPR or gene editing.

Dr. Sharman:
Yeah.

Andrew Schorr:
So do you think this gene editing will play a role in CLL?

Dr. Sharman:
Hoo, boy. You know, I think that probably dovetails with the question you didn’t ask, which is about CAR‑T cells. I think CRISPR, for members of the audience who may not be familiar with it, is a highly efficient, highly directed way of making genetic manipulation within cells,

and with a lot of the gene therapy that’s been done over the years we sort of randomly insert genetic material into cells to sort of reprogram them. That’s sort of the classic way of doing gene therapy. The problem with that is there are parts inside the genome that don’t like to be broken, and so the field really was set back a number of years when there were some early cases of leukemia caused by gene therapy.

And so what CRISPR does is it does allow you to make very targeted genetic modifications so that you can precisely put in new genetic material sort of wherever you want it. And I think that in the context of CAR‑T therapy there’s now goals to make it much more off the shelf than this sort of highly manufactured thing, and that’s where I would see CRISPR having the most likely early role.

Andrew Schorr:
Okay. So CAR‑T, chimeric antigen receptor T‑cell therapy, taking a virus, I think, and combining it with stuff for your T‑cells, targeting your CLL. So Lynne just asked, she’s 71, would somebody older like that‑‑tomorrow is my 68th birthday, folks‑‑would we be candidates for CAR‑T should we need it?

Dr. Sharman:
Well, I need to articulate some of my limitations as a community practice oncologist, thus far the CAR‑T research has been sort of in the exclusive purview of academic centers, so I haven’t had the chance to do it yet. That having been said, we are working with a variety of sponsors to get such a program up and running.

However, I will say there’s a lot of enthusiasm in CLL because the original New England Journal of Medicine paper that described CAR‑T was done in both pediatric acute leukemia and adult chronic lymphocytic leukemia, and it is now approved by the FDA for the pediatric ALL, acute lymphoblastic leukemia. It is not approved for CLL. And part of that‑‑there’s a lot of reasons why it doesn’t work as well in CLL as it does in other diseases, and I think that the‑‑it’s okay that this is moving a little bit more slowly in the CLL field because I think we’re getting a lot of benefit of accumulating knowledge in how to make it work best in CLL. I think it will become an important therapy in CLL.

Keep in mind that the toxicity of chimeric T‑cell is significant, and the possibility of neurotoxicity or this syndrome that looks a little bit like sepsis that’s not sepsis but it looks like it in a lot of ways, what we call cytokine release syndrome make this a therapy where caution is advised.

And so if it’s something you’re thinking about I would say go get yourself seen in your very specific circumstances with somebody doing this in research studies and decide if it’s right for you.

Andrew Schorr:
Okay. And we’ll have‑‑in other programs we’ll talk about CAR NK research that’s going on. Lot to talk about, maybe at ASH, folks. Dr. Sharman will be at the American Society of Hematology meeting, the ASH meeting here in San Diego in a couple of months. We’ll have coverage from that as these new areas come out.

Now let’s go back to the basics before the end, Jeff, and this that is flu season coming up.

Dr. Sharman:
Yes.

Andrew Schorr:
And there’s also a shingles vaccine. And also some people related to hepatitis B.

What are you telling your patients about vaccines? My friend Jeff Folloder said somebody at MD Anderson had them maybe getting two flu shots.

Dr. Sharman:
Yeah.

Andrew Schorr:
So first of all, flu shots, and do we need more than one? And what about these other shots?

Dr. Sharman:
Yeah, so starting with flu I would encourage all my patients CLL patients to get flu shots. The response is nearly universal. Everybody always says, well, I got a flu shot and I still got sick. A flu shot does not prevent all illness. Flu prevents flu. And patients with CLL get more complications from flu because their immune system has a cancer in it. So CLL is a cancer of the immune system, so to whatever extent you can give yourself a head start to fight off flu I would encourage patients to do so.

Andrew Schorr:
More than one shot?

Dr. Sharman:
Well, so I will say that patients with CLL generally have less of a response to a flu vaccine than somebody without CLL.

So you don’t get as much protective benefit if you have CLL as somebody without it. I don’t think, at least, I’m not familiar with data that says two flu shots are better than one. It may be out there and I’m not aware of it, but I mean I could understand why you might. It at least biologically makes sense.

Andrew Schorr:
And the shingles vaccine?

Dr. Sharman:
Yeah, so very few clinic days go by where I don’t curse shingles at least once. For anybody who has had shingles you know it can hurt really badly, and there is this condition called post herpetic neuralgia, which is a sort of a lingering pain syndrome that can go on for years for patients who have had shingles and can be a life altering pain. And so, again, I think whatever head start you can give your immune system it’s worth doing.

And I guess the reason why I curse shingles so frequently is because it does seem to go part and parcel with lymphomas and CLL. Again, you have a cancer of the immune system. The immune system doesn’t work as well, and, boy, I can’t count the number of times where somebody gets shingles just as their CLL is acting up and then it delays treatment, or somebody is going through treatment with a lot of pain as a result.

Andrew Schorr:
So you’re not worried about the vaccine?

Dr. Sharman:
No. Not only am I not worried I highly encourage it. But I would point out that the old vaccine was a live virus, and there were problems giving that to patients with CLL. There is a new dead virus, Shingrix, that’s in short supply.

Andrew Schorr:
Okay. Well, we’re going to wrap up. I want to just help everybody understand what I alluded to a minute ago, the world series of blood cancer‑related discussions where a lot of data, and, Jeff, you may have data presented there, is the American Society of Hematology meeting which is near me in San Diego in December and about 30‑, 40,000 people come and discuss all this.

So stay tuned. We’ll be doing programs from there, and we’ll bring you updates. Dr. Jeff Sharman, thank you so much for being with us once again.

Dr. Sharman:
My pleasure, Andrew. Thank you for your time.

Andrew Schorr:
All right. And this is what we do. Thanks to the Patient Empowerment Network so devoted to this. We’re happy to help from Patient Power, and thanks to the supporters for this program. They had no editorial control, but they believe in education. That’s AbbVie Incorporated and also Pharmacyclics.

I’m Andrew Schorr. Remember, knowledge can be the best medicine of all.

Please remember the opinions expressed on Patient Empowerment Network are not necessarily the views of our sponsors, contributors, partners or PEN. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.